Cancer immunotherapy is in the midst of a major paradigm shift from an approach primarily focused on attacking tumor cells to a strategy also targeting the tumor microenvironment (TME). This strategy is designed for the use of combination therapies, several of which are reviewed here. Particular emphasis is placed on targeting such components of the TME as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) overexpressing specific therapy targets such as Legumain, an asparaginyl endopeptidase, proto-oncogene Fra-1, transcription factor Stat3 and fibroblast activation protein (FAP) as well as HER-2, respectively. The use of DNA vaccines directed against some of these targets overexpressed on both breast tumor cells as well as TAMs and CAFs in the TME results in the elimination of tumor growth, progression, metastasis and recurrence in mouse tumor models. This type of cancer therapy is significantly improved in efficacy by a strategy specifically designed to combine immunotherapies, including DNA vaccines, with a novel chemotherapy featuring highly effective nanoparticle-mediated drug delivery, specifically targeted to tumor cells as well as key components of the TME, leading to its modulation and subsequent elimination of tumor growth, metastasis, and, most importantly, suppression of tumor recurrence.